5-hydroxythiazolidines



United States Patent O1 3,522,266 Patented July 28, 19707-amino-cephalosporanic acid corresponds to the for- 3,522,266 mulaS-HYDROXYTHIAZOLIDINES 0 0 H Robert Burns Woodward, 12 Oxford St.,

Cambridge, Mass. 02138 No Drawing. Filed Aug. 22, 1966, Ser. No. 573,891O=CN CCH2OOO-CH Claims priority, application Switzerland, Sept. 10,1965, H2

12,623/65; Dec. 9, 1965, 16,970/65, 16,972/65; Jan. 5 13, 1966, 447/66;Feb. 3, 1966, 1,529/ 66 27/00 HZN s XVI C07d 91/16: 99/ 24; C091Derivatives are in the first place N-acyl compounds in 260 '306'7 5Clalms 10 which the acyl radicals are primarily those of active N- acylderivatives of 7-amin0-cephal0sporanic acid, such as the thienylacetyl,e.g. Z-thienylacetyl, cyanoacetyl, chlor- ABSTRACT OF THE DISCLOSUREethylcarbamyl or phenylacetyl radical, or acyl radicals that 5 h d d b dare easy to eliminate, such as the residue of a semi-ester of y roxyt fm PrePare y treatmg ,Saturate carbonic acid, for example, the tertiarybutyloxycarbonyl CYCllC a-hydrazmo thioether, 1n WhlCh the hydrazinogroup residue is N,1\ l-di substituted by esterified carboxyl groups,with The synthesis of this compound, which is important to an oxldatlonreagent capablfi of furmshlng an acyloxy the manufacture of valuablemedicaments, and of its derivgroup which y y compounds hydmlyled to theatives is based on the conception to use a 3,5-unsubstihydroxy compound.The S-hydroxy thlazolidines are useful tuted 2,2-disubstitutedthiazolidine 4-carboxylic acid, for in the synthesis of7-amino-cephalosporanic acids. example, a compound of the formula Q0011CH-CHz The present invention provides a method procedure for H v N S themanufacture of acyloxy compounds and the corresponding hydroxyderivatives, which was used in the production of valuable intermediateproducts and especially H3O C 3 I 111 first. PTOdUQtiOH 2 Synthetic p asthe starting material and to carry out the novel synsporanic acid andits derivatives, and lends itself par- 3 thesis, for example, accordingto the following Scheme of ticularly well to this peculiar synthesis.formulae:

COOH COOH COOCHs CHCH2 CH3 /C'HCH2 CH3 oH oH2 HN S CHa- --OCN S CHa(O-C-N S /C\ Ha /C H: O /C\ CH: CH2 CH3 CH3 CH3 CH3 I II III l+IfiTCOOCHaN-COOCH:

COOCH: OCOCII: COOCHa N-NHCOOCHs CH3 CHCH CH3 (EH-0H & Pb(OCOCH3)4 I0113- O("3N\ /S CHa(|3O-( 'J-N\ S H 0 o CH3 O CH3 CH3 CH3 CHs V IV oooomOH QOOCH: Na CH3 err-cg (3H3 JH-C H CH3(:JO(lll-N\ /S CHaCO--CN S CH3 0o H3 o CH3 CH3 0 s CHa VI VII o=o1 IH oooorn .NHZ CH3 o11 o AK 0 H) (3H3orb-0H oH3- :o N s e CH3CO-'CN s H3 0 o (3H3 d o CH3 CH3 CH3 CH3 VIII 3The compound IX is converted into the desired 7-aminocephalosporanicacid and its derivatives as follows:

benzoate, as well as thallium-III-acylates, such as thallium-III-acetate, or mercury-II-acylates, such as mercury-II- /CH0 o=oI 10-0110 IX CIICCHZOOCCH=C OH; CH-CH 011011 0110 H3c-oo-oN s H CH3 0 /C\CH2 CH2 1 laCCOOH 0000112001; 00001120018 (m 41H 1) Aeylation O=CN/oo1120ooo113 2) Reducmn 0=c -1;1 OI-CH0 3) Acetylation OH CE CH Acyl-NHs HZN l XIII XII oooomooa (10011 O=CN/ CCH2OCOOHa Reductm O=C-No-omoooom fill-(3H /CH2 oft-0E /CH2 Acyl-NH s Acyl-NH s XIv XV XvI Thecompounds of the Formula X used as the interacetate. If desired, theseoxidants may be formed in situ,

mediate is manufactured in the following manner:

NaOCE COOCHzCCla OCH COOCHzCCla CH O=CH /CH HOH OHC OCH 4O OCHCOOCHzCCla C: H OCH X The above mentioned compounds, which are valuableintermediates, for example the compounds of the Formulae V and VI, areunexpectedly obtained when a saturated cyclic a-hydrazino-thioether, inwhich the hydrazino group is N,N'-disubstituted by esterified carboxylgroups, for example, the compound of the Formula IV, is treated with anoxidation reagent capable of furnishing an acyloxy group and, ifdesired, in a resulting saturated cyclic uacyloxy-thioether the acyloxygroup is converted into the hydroxyl group, and/or, if desired, in aresulting compound a substituent is converted into another, and/ or ifdesired a resulting mixture of isomers is resolved into its componentisomers.

Acyl radicals of an acyloxy group furnished by the oxidation reagentduring the reaction are the acyl radi cals of organic carboxylic acids,especially of aliphatic carboxylic acids, such as alkane carboxylicacids, especially lower alkane carboxylic acids, in the first place 6acetic acid or propionic acid, or of aromatic carboxylic acids, such asbenzoic acid. These acids are unsubstituted, but may carry furthersubstituents, such as lower alkyl or lower alkoxy groups or halogenatoms or pseudohalogen groups, such as trifluoromethyl groups.

Oxidation reagents capable of furnishing acyloxy groups are in the firstplace heavy metal acylates with oxidizing properties. Particularlysuitable are lead tetraacylates and especially lead tetraacetate, aswell as lead tetrapropionate, lead tetrastearate, lead tetrabenzoate,lead tetra-3-bromofor example, by reacting lead dioxide or mercuricoxide with an organic carboxylic acid, such as acetic acid, and/ or, ifdesired, used in the presence of a buffer such as sodium acetate.

Further oxidants capable of supplying acyloxy groups are acylhypohalites, which are usually formed in situ, for example, by reactionof halogen, especially bromine or iodine, on organic carboxylic acids orof salts thereof, such as mercury-II-acylates, for example, mercury-II-acetate (which may likewise be formed in situ, for example, frommercury-II-oxide in the presence of glacial acetic acid) or of silveracylates, such as silver acetate, as well as by the reaction of otheragents yielding positive halogen, such as N-halogenoamides or -imides,such as N-bromoacetamide, N-succinimide or N-bromohydantoin on organiccarboxylic acids, such as the above-mentioned carboxylic acids,especially acetic acid.

According to the present invention the reaction may consist, forexample, in treating the starting material with the appropriatequantity, that is to say at least 2 mol equivalents, of the oxidationreagent capable of furnishing acyloxy groups, conventionally in thepresence of a suitable diluent, such as benzene, acetonitrile or aceticacid, at room temperature, while cooling or preferably while heating, ifnecessary, in an inert gas and/or under increased pressure, theconversion into the desired acyloxy-products being carried out stepwiseor directly.

Conversion in the resulting products of the acyloxy groups into the freehydroxyl groups is carried out by hydrolysis, alcoholysis,hydrazinolysis or aminolysis. Under certain circumstances the isolationof the acyloxy compound may not be necessary, as it is converted undersuitable reaction conditions directly into the desired hydroxy compound.The hydrolysis may be carried out in the absence or preferably in thepresence of a basic hydrolysing agent, such as an alkali or alkalineearth metal hydroxide, for example, sodium or potassium hydroxide, or analkali metal or alkaline earth metal carbonate or hydrogen carbonate,for example sodium or potassium carbonate or hydrogen carbonate, or ofan organic base such as pyridine or triethylamine; it may also takeplace when the starting material is treated with an adsorbent which ischarged with water or just moist, such as 21 diatomaceous earthpreparation (Florisil). Alcoholysis, for example by means of a loweralkanol such as methanol or ethanol, may be carried out in the presenceof a transesterifying catalyst, such as a metal salt, for example alkalimetal salt, such as sodium or potassium salt, or of an ammonium salt ofa carboxylic acid, especially of a lower alkane-carboxylic acid, such asacetic acid, or of an arylcarboxylic acid, such as benzoic acid.Hydrazinolysis and aminolysis are achieved by treatment with hydrazineand with ammonia or a primary or secondary amine, respectively.

The above-mentioned reactions are carried out in the presence or absenceof a diluent (in which case the splitting reagent, for example a loweralkanol, may also serve as solvent), if necessary while cooling orheating and/or in an inert gas and/or under superatmospheric pressure.

It was also unexpectedly found, that, when starting with a2,2-disubstituted L-3-acyl-5a-acyloxy-thiazolidine- 4-carboxylic acid ora functional derivative thereof, as well as a corresponding2,2-disubstituted L-3-acyl-5B- acyloxy-thiazolidine-4-carboxylic acid ora functional derivative thereof, or a mixture of the two isomers as thepreferred starting materials, the 2,2-disubstitutedL-3-acyl-Sfl-hyclroxy-thiazolidine-4-carboxylic acids and theirderivatives, respectively, are obtained almost exclusively.

In a resulting compound with a free hydroxyl group, the latter can beconverted into an acyloxy group, for example, by treatment with asuitable derivative of an organic carboxylic acid, such as a halide oran anhydride thereof, or by converting the hydroxy group into a reactiveesterified hydroxy group, such as a halogen, e.g. chlorine or bromineatom (for example, by treatment with a suitable acid halide, e.g.phosgene) or an organic sulfonyloxy group, e.g. methane sulfonyloxy orp-toluene sulfonyloxy group (for example, by treatment with a suitableorganic sulfonic acid halide) and treatment of the resultingintermediate with an organic carboxylic acid or preferably a salt, suchas an alkali metal salt thereof.

Substituents present in a resulting compound may be converted in knownmanner into other Substituents. Thus, a resulting acid derivative, suchas an ester, can be converted into the free acid without removing theacyl group, especially a readily eliminatable acyl group, such as thetertiary butyloxycarbonyl group, in position 3. Thus, a carbo-loweralkoxy, such as the carbomethoxy group, can be hydrolyzed to furnish thefree carboxyl group by treatment with a dilute alkali metal hydroxide,such as potassium hydroxide, solution; this conversion into the freecarboxyl group may, if desired, be carried out during the splitting ofthe acyloxy group. Carbodiphenylmethoxy groups may be converted intofree carboxyl groups under acidic conditions, for example, in thepresence of catalytic amounts of an acid, such as trifiuoroacetic acid.Then, a carboxyl group esterified with a 2,2,2-trihalogenoethanol,especially with 2,2,2-trichloro-ethanol, can be converted in a peculiarmanner into the free carboxyl group by means of a reducing agent.Suitable reagents are chemical reducing agents, such as nascenthydrogen, obtained, for example, by the action of metals, metal alloysor amalgams upon hydrogen donors, such as zinc, zinc alloys, forexample, zinc copper, or zinc amalgam in the presence of acids, such asorganic carboxylic acids, for example, acetic acid, or of alcohols, suchas lower alkanols, an alkali metal amalgam, for example, sodium orpotassium amalgam or aluminium amalgam, in the presence of moist etheror of lower alkanols, furthermore, alkali metals, for example, lithium,sodium or potassium, or alkaline earth metals, for example calcium, inliquid ammonia, if desired or required, with the addition of alcohols,such as a lower alkanol. Furthermore, an ester with a2,2,Z-trihalogeno-ethanol, such as 2,2,2-

6 trichl oroethanol may also be converted into the free acid bytreatment with strongly reducing metal salts, such aschromium-II-compounds, e.g. chromium-II-chloride or chromium-II-acetate,preferably in the presence of aqueous media containing water-miscibleorganic solvents, such as lower alkanols, lower alkane carboxylic acidsor ethers, for example, methanol, ethanol, acetic acid, tetrahydrofuran,dioxan, ethyleneglycol dimethyl ether or diethyleneglycol dimethylether.

A free carboxyl group present in a resulting compound can be convertedin known manner into its functional derivatives, such as its esters,amides, hydrazides or azides. It can be esterified, for example, bytreatment with a diazo compound, such as a diazo-lower alkane, forexample diazomethane or diazoethane, or a phenyl-diazolower alkane, forexample, diphenyl-diazomethane, or by reaction with a hydroxy compoundsuitable for esterification, for example an alcohol, a phenol compoundor an N-hydroxy-nitrogen compound, for example, a hydroxamic acid, inthe presence of an esterifying agent, such as a carbodiimide, forexample, dicyclohexyl carbodiimide, or of carbonyl diimidazole or by anyother known and suitable esterifying process, such as reaction of a saltof the acid with a reactive ester of the hydroxy compound, especially ofan alcohol, and a strong inorganic acid or strong organic sulphonicacid, if desired, in the presence of a salt-forming base. Amides areprepared in known manner, sulphonylamides at the acyloxy stage, forexample, by treating the free carboxylic acid with asulphonylisocyanate.

A functionally modified carboxyl group in a resulting compound can beconverted in known manner into another functionally modified carboxylgroup, for example, into an esterified carboxyl group bytransesterification, such as treatment, with a hydroxy compound in thepresence of a transesterification catalyst. Furthermore, esters andespecially activated esters, for instance, esters withN-hydroxy-nitrogen compounds, or anhydrides formed with halo-genoformicacid esters, can be converted by reaction with other hydroxy compounds,such as alcohols or phenol compounds, as well as with ammonia, or withprimary or secondary amines or hydrazines into other esters and amidesor hydrazides, respectively. In a resulting amide or hydrazide compoundwith a nitrogen atom containing hydrogen, such nitrogen atom cansubsequently be replaced, for example, by treatment with a reactiveesterified alcohol, or, primarily in an amide or hydrazide compound ofthe acyloxy series, by treatment with a carboxylic or sulphonic acidderivative, such as an acid halide or by means of another suitablereagent. An N-unsnbstituted amide derivative of the acyloxy series canbe converted into the corresponding nitrile, for example, bydehydration.

A resulting mixture of isomers can be resolved into the individualisomers in known manner, for example by fractional crystallization,adsorption chromatography (column or thin-layer chromatography) or byother methods. Resulting racemates can be resolved into the antipodes byforming a mixture of diastereoisomeric salts with optically active,salt-forming agents, separating the mixture into the diasteroisomericsalts and conversion of the isolated salts into the free compounds.

The compounds obtained by the present process are saturated cyclica-acyloxy-thioethers, for example, S-acyloxy-thiazolidines, andespecially 2,2-disubstituted 3-acyl- S-acyloxy-thiazolidine-4-carboxylicacids and functional derivatives thereof, such as the compounds of theformula Va as well as saturated cyclic a-hydroxy-thioethers, such asS-hydroxy-thiazolidines, and particularly 2,2-substituted3-acy1-S-hydroxy-thiazolidine-4-carboxylic acids and functionalderivatives thereof, such as the compounds of the Formula VIa Act-N SVIa where Ac represents an acyl radical, especially the acyl radical ofan active N-acyl derivative of cephalosporanic acid, such as thethienylacetyl, e.g. Z-thienylacetyl, chlorethylcarbamyl or phenylacetylradical, or an easily eliminable acyl radical, such. as the residue of acarbonic acid semiester, for example, the tertiary butyloxycarbonylresidue, Ac represents the acyl radical of an organic carboxylic acid,such as the acyl radical of the acyloxy group supplied during thereaction, such as the acyl radical of an aliphatic carboxylic acid, forexample, of an alkane carboxylic acid, such as a lower alkane carboxylicacid, primarily acetic acid or propionic acid, or of an aromatic acid,such as benzoic acid, which acids are unsubstituted or may containfurther substituents, such as lower alkyl or lower alkoxy groups orhalogen atoms or pseudohalogens, such as trifiuoromethyl groups, Xrepresents the disubstituted carbon atom of the thiazolidine ring and Ris a free or functionally modified carboxyl group.

The residue X- represents primarily the group of the formula where R andR each stands for a hydrocarbon residue, especially an aliphatichydrocarbon residue, such as a lower alkyl, for example, ethyl,n-propyl, isopropyl or preferably methyl, or an aromatic groupespecially a phenyl group, or an araliphatic hydrocarbon residue,especially phenylalkyl, for example benzyl or phenylethyl groups, aswell as functionally converted, particularly esterified carboxyl groups,such as carbo-lower alkoxy, e.g. carbomethoxy or carbethoxy groups, or Rand R together may represent a bivalent hydrocarbon residue, especiallybivalent aliphatic hydrocarbon residue such as a lower alkylene group,for example 1,4-butylene or 1,5- pentylene, as well as a phthaloylgroup, or an x0 or thiono group. The above-mentioned hydrocarbonresidues are unsubstituted or may be substituted, for example by loweralkyl, such as methyl or ethyl, by lower alkoxy, such as methoxy orethoxy groups, halogen such as fluorine, chlorine or bromine atoms,halogenoalkyl, such as trifluoromethyl groups, or by other suitablegroups.

The group R is a free or preferably a functionally modified carboxylgroup, especially an esterified carboxyl group. The latter is esterifiedwith any hydroxy compound suitable for esterifying carboxylic acids,such as with aliphatic alcohols, for example, alkanols, particularlylower alkanols, for example, methanol, ethanol, n-propanol or tertiarybutanol, or with cycloaliphatic alcohols, such as cycloalkanols, forexample, cyclohexanol, or with araliphatic alcohols, such asphenylalkanols, for example benzyl alcohol or diphenylmethanol, or withphenol compounds especially phenol, or with N-hydroxy-nitrogencompounds, such as 'hydroxamic acids, for example, N- hydroxycarbamicacid esters, such as its methyl ester, or with N-hydroxy-imides, forexample, N-hydroxysuccinimide; the above-mentioned hydroxy compounds maybe unsubstituted or substituted by lower alkyl, lower alkoxy, nitro ortrifiuoromethyl groups or especially by halogen atoms or other groups.Substituted hydroxy compounds particularly suitable for esterifyingcarboxylic acids are halogenated lower alkanols, such as2,2,2-trichlorethanol.

Other functionally modified carboxyl groups R are, for example,nitrogen-containing functionally modified carboxyl groups, such ascarbamyl groups which may be unsubstituted or monoor disubstituted onthe nitrogen atom by aliphatic, alicyclic, aromatic or araliphatichydrocarbon residues or heterocyclic residues of aromatic character,which may optionally contain lower alkyl groups or free, esterified oretherified hydroxyl groups, such as lower alkoxy, aralkoxy, loweralkanoyloxy or aroyloxy groups or halogen atoms, nitro ortrifluoromethyl groups as substituents, such residues being lower alkyl,cycloalkyl, phenyl, phenyl-lower alkyl, phenyllower alkylidene orpyridyl residues, or by free, etherified or esterified hydroxyl groups(such as those mentioned above), by phosphoriferous residues or by acylradicals, such as the radicals of carboxylic acids, for example,residues of carbonic acid semi-esters or semi-amides or lower alkanoylresidues, or of sulphonic, such as arylsulphonic acid, for example,phenylsulphonyl residues, as well as nitrile groups or azidocarbonylgroups, as well as hydrazinocarbonyl or azocarbonyl groups which may bemono or polysubstituted on the nitrogen, for example, by theabove-mentioned substituents of the carbamyl group.

The present invention includes also any modification of the presentprocess in which an intermediate obtained is used as starting materialand any remaining step or steps is or are carried out with it. Forexample, saturated cyclic thioethers may be formed as intermediates andisolated or converted into each other, which contain in OC-pOSltlOI'l ahydrazono group substituted by an esterified carboxyl group, or anacyloxy group together with an azo group substituted by an esterifiedcarboxyl group; such intermediate compounds are, for example,S-hydrazono-thiazolidines or 5-acyloxy-S-azo-thiazolidines, in which thehydrazono and the azo group are substituted by an esterified carboxylgroup, especially 2,2-disubstituted 3 acylS-hydrazono-thiazolidine-4-carboxylic acids and 2,2. disubstituted3-acyl-5-acyloxy-5-azo-thiazolidine-4- carboxylic acids, in which thehydrazono group and the azo group, respectively, are substituted by anesterified carboxyl group, and their functional derivatives, such as thecompounds of the formulae in which Ac AC2, R and X have the abovemeanings, and R represents the resiude of an alcohol, for example, theresidue of one of the alcohols mentioned above as being suitable foresterifying the carboxyl groups R especially the residue of an aliphaticalcohol, such as a lower alkanol or a substituted, preferablyhalogenated, lower alkanol. Such intermediates can be converted into thedesired products by suitable measures either directly or stepwise. Thus,for example, a saturated cyclic thioether, which is substituted ina-position by a hydrazono group containing the esterified carboxylgroup, can be converted into the desired acyloxy compound by additionaltreatment with an oxidation reagent capable of furnishing the acyloxygroup. The desired acyloxy compound is also obtained when a saturatedcyclic thioether, which contains in the a-position an acyloxy grouptogether with an azo group with the esterified carboxy substituent, istreated, for example, with a hydrolyzing agent, especially a weaklyacidic or weakly basic agent, such as potassium acetate in the presenceof acetic acid or sodium hydrogen carbonate in the presence of methanol,or with water, preferably on a supporting sub stance, such as adiatornaceous earth preparation (Florisil). Furthermore, from asaturated cyclic thioether, which contains in the tat-position anacyloxy group, together with an azo group having an esterified carboxysubstituent, a saturated cyclic thioether substituted in the a-positionby a hydrazono group containing the esterified carboxyl group can beformed, for example, by treatment with zinc and acetic acid.

The invention includes also any modification in which the process isdiscontinued at any stage thereof, or in which starting materials areused in the form of derivatives, for example of salts, or are formedduring the reaction.

Preferred use is made of those starting materials and reactionconditions which give rise to the preferred compounds mentioned above.

The starting materials used in the above process can be prepared, forexample, by the process described in patent application Ser. No.573,816, filed Aug. 22, 1966 and now US. Pat. No. 3,449,336.

The compounds obtained according to the present invention can beconverted into 7-amino-cephalosporanic acid and its derivatives asillustrated by the reaction scheme; this conversion may be carried out,for example, by the process described in the following patentapplications:

Ser. No. 573,865, filed Aug. 22, 1966; Ser. No. 573,815, filed Aug. 22,1966; Ser. No. 573,886, filed Aug. 22, 1966; Ser. No. 573,866, filedAug. 22, 1966; and Ser. No. 573,876, filed Aug. 22, 1966.

The following examples illustrate this invention.

EXAMPLE 1 A solution of 1 g. of L-2,2-dimethy1-3-tertiarybutyloxycarbonyl-Sfl-(N,N'-dicarbomethoxy hydrazine)thiazolidine-4-carboxylic acid N-methyl-N-phenylsulphonylamide in 50 ml.of absolute benzene is treated with 1.6 g. of vacuum-dried leadtetraacetate, and the mixture is stirred for 45 minutes under reflux.0.05 ml. of distilled ethyleneglycol is added, and after minutes themixture is filtered with a filter aid (Hyflo) and rinsed with benzene.The yellow filtrate is evaporated to dryness and the crystalline residuetriturated with ether and pentane, cooled and filered, to yieldL-2,2-dimethyl-3-tertiary butyloxycarbonyl-S-acetyloxy 5carbomethoxy-azo-thiazolidine-4-carboxylic acidN-methyl-N-phenylsulphonylamide of the formula in almost colourlesscrystals which melt at 161-163 C. after recrystallization from methanol.Optical rotation [a] =-32- 1 (c.=1.070 in chloroform). Infraredabsorption bands (in methylenechloride) at 5.69, 5.90, 6.00, 7.35, 8.10,8.34, 8.57 and 9.24 2. Ultraviolet absorption bands (in methylenechloride) k 225 mu (s=13,000), 260 mg =1500), 267 mu =1770 and 274 mp.(E:1600) in ethanol, and k at about 380 my (e=about 7080).

A solution of 0.663 g. of L-2,2-dimethyl-3 tertiarybutyloxycarbonyl-S-acetoxy-S carbomethoxyazo thiazolidine-4-carboxylicacid N-methyl-N-phenylsulphonylamide in 100 ml. of benzene is mixed withg. of a diatomaceous earth preparation (Florisil) and stirred for 45minutes at room temperature; with evolution of gas the colour of thesolution changes from deep yellow to light yellow to colourless. Themixture is then filtered, the residue washed with benzene and with 70 to100 ml. of ethyl acetate, and the organic solutions are evaporated. Theproduct is chromatographed on 35 g. of a diatomaceous earth preparation(Florisil). After preliminary washing with 150 ml. of benzene, the crudeproduct is eluted with 350 ml. of benzene containing 1% of ethylacetate. A mixture, which likewise consists predominantly of the desiredproduct, is eluted with another 200 ml. of the same solvent mixture. Thecrude product is recrystallized from a mixture of ether and pentane, toyield semi-crystalline to amorphous L-2,2-dimethyl-3-tertiarybutyloxycarbonyl- 55-acetyloxythiazolidine-4-carboxylic acid N-methyl N-phenylsulphonylamide of the formula melting at 115 C. Optical rotation[a] =+72i1 (c.=0.922 in chloroform). Infrared absorption bands (inmethylenechloride) at 5.74, 5.83, 7.36, 8.23, 8.60 and 1038 Ultravioletabsorption bands (in ethanol) A 226 m 12,950), 260 mp. (e=1400), 267 mu(e '-l550) and 273 m (e=1250).

When the above chromatograrn is further eluted with ml. of benzenecontaining 2% of ethyl acetate, a mixture is obtained which consistspredominantly of L- 2,2-dimethyl-3-tertiary butyloxycarbonyl-5uacetyloxythiazolidine-4-carboxylic acid N-methyl N phenylsulphonyl amideof the formula Ha a of which a further quantity is obtained with 100 ml.of benzene containing 2% of ethyl acetate and with 100 ml. of benzenecontaining 5% of ethyl acetate in a rather uniform state and with 50 ml.of benzene containing 5% of ethyl acetate and 100 ml. of benzenecontaining 10% of ethylacetate as a partially crystalline mixturetogether With the corresponding 5,8-hydroxy and 5a-hydroxy compounds.After recrystallization from a mixture of methylenechloride and etherthe product melts at 220-221 C. Optical rotation [a] =-214- -1(c.-=0.889 in chloroform). Infrared absorption bands (inmethylenechloride) at 5.75, 5.86, 5.97, 7.40, 8.25, 8.62 and 10.68,u.

The L-2,2-dimethyl-3 tertiary butyloxycarbonyl 5-'acetyloxy-5-carbomethoxyazo-thiazolidine 4 carboxylic acidN-methyl-N-phenylsulphonylamide, which can also be converted into thedesired product by treatment with a diatomaceous earth preparation(Florisil) in benzene for 17 hours at room temperature, followed byelution with ethyl acetate, is also obtained in the following manner:

A mixture of 0.02 g. of L-2,2-dimethyl-tertiarybutyloxycarbonyl-5-N-carbomethoxyhydrazono thiazolidine- 4-carboxylicacid N-methyl-N-phenylsulphonylamide and 1 ml. of benzene is stirred for2 hours at room temperature with a solution of 0.016 g. of leadtetraacetate in 1 ml. of benzene. The excess of the oxidation reagent isdecomposed by adding one drop of ethyleneglycol, and the reactionmixture is diluted with benzene and Washed with water. The benzenesolution furnishes L-2,2-dmethyl-3- tertiary-butyloxycarbonyl-S-acetoxy5 carbomethoxyazo-thiazolidine-4-carboxylic acidN-methyl-N-phenylsulphonylamide which is identified by thin-layer chromatography and its infrared spectrum.

The L-2,2-dimethyl-tertiarybutyloxycarbonyl-5-N'-carbomethoxyhydrazono-thiazolidine-4 carboxylicacid N- methyl-N-phenylsulphonylamide used above can be prepared in thefollowing manner:

A solution of 0.193 g. of crystalline -L-2,2-dimethyl-3- tertiarybutyloxycarbonyl-S-acetoxy-S carbomethoxyazothiazolidine-4-carboxylicacid N-methyl N phenylsulphonylamide in 10 ml. of acetic acid and 0.1m1. of water is mixed with 2 g. of zinc powder and the mixture isstirred for 1 hour at room temperature, and filtered; the residue iscautiously washed with benzene, the filtrate diluted to a volume ofabout 120 ml. with benzene and repeatedly Washed with water, the washingbeing washed back with benzene. The combined benzene extracts areevaporated and the residue chromatographed on 10 g. of a diatomaceousearth preparation (Florisil). Benzene, benzene containing 2% of ethylacetate, and 40 ml. of benzene containing 5% of ethyl acetate, elutemixtures of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5p-acetyloxythiazolidine-4-carboxylic acidN-methyl-N-phenylsulphonamide with the corresponding 5a-acetyloxycompound. A further quantity of 40 ml. of benzene containing 5% of ethylacetate, and 60 ml. of benzene containing 10% of ethyl acetate, elute2,2-dimethyl-tertiary butyloxycarbonyl-5-N-carbomethoxyhydrazonothiazolidine 4- carboxylic acid N-rnethyl-N-phenylsulphonylamide of theformula HaC-C-O-C-N l H CHa o HaC CH3 which, after crystallization fromether, melts at 163-165" C. Optical rotation [oz] =0il (c.'=1.015 inchloroform). Infrared absorption bands (in methylenechloride) at 2.99,5.70, 5.82. 5.93 (shoulder), 6.20, 6.67, 7.40, 8.17, 8.55 and 9.35 4.

EXAMPLE 2 A mixture of 3 ml. of glacial acetic acid and 0.15 g. ofanhydrous sodium acetate is stirred for 35 minutes at 80 C., then 0.05g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-S-acetoxy-S-carbomethoxyazo thiazolidine- 4-carboxylicacid N-methyl-N-phenylsulphonylamide is added and the whole is stirredfor another 45 minutes at 80 C.; after 30 minutes the initially yellowmass loses its colour. The reaction product is isolated by pouring thebatch into Water, and extraction with benzene yields a crystallinemixture of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-SyQ-acetyloxy-thiazolidine-4-carboxylic acid N-rnethyl-N-phenylsulphonylamide and the corresponding ot-acetyl product.

Alternatively, the reaction may be carried out by treating the startingmaterial with triethyl ammonium acetate in hot benzene for 17 hours.

EXAMPLE 3 A solution of 0.388 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5 acetoxy 5 carbomethoxyazothiazolidine-4-carboxylicacid N methyl-N-phenylsulphonylamide in ml. of methylene chloride and 10ml. of methanol is mixed with 0.15 g. of anhydrous sodium carbonate andthen stirred for 30' minutes at room temperature. Gas is evolved and theyellow colour of the solution disappears. The solution is diluted withmethylene chloride, washed with water, dried and evaporated to yield acrystalline mixture of L-2,2-dimethyl-3- tertiarybutyloxy-carbonyl-Spi-acetyloxy thiazolidine-4- carboxylic acidN-methyl-N-phenylsulphonylarnide and of the corresponding 5u-acetyloxyproduct.

EXAMPLE 4 A solution of 0.92 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-SB-(N,N' dicarbethoxy hydrazine)-thiazolidine-4-carboxylic acid methyl ester in 16 ml. of acetonitrile istreated with 0.34 g. of anhydrous sodium acetate and 1.4 g. of leadtetraacetate free from acetic acid. The mixture is heated for 45 minutesat 60 C., then evaporated under vacuum and the residue is triturated 3times with 20 ml. of hexane and with 5 ml. of methylene chloride. Thecombined filtrates are concentrated under reduced pressure to yield ayellow oil which is again dissolved in 6 ml. of acetonitrile and treatedwith 1.45 g. of lead tetraacetate. The reaction mixture is heated for 1hour at 60 C., the lead diacetate formed is filtered off, the filtrateis evaporated and the residue is taken up in 5 ml. of methylene chlorideand 30 ml. of hexane. After a few minutes the extract is filtered, thefiltrate once more evaporated under vacuum and the yellow oily productis chromatographed on 42 g. of anhydrous silica gel. The column ispre-eluted with 350 ml. of benzene, then with ml. of benzene containing5% of ethylene acetate. The next three fractions eluted with 50 ml. eachof this solvent mixture contain the desired L-2,2-dimethyl- 3-tertiarybutyloxycarbonyl 5B acetyloxy-thiazolidine- 4-carboxylic acid methylester of the formula QOOOHs which is obtained in crystalline form whenin the product obtained from the second of these three fractions thedeposited crystals are freed from the oily material by being Washed withpentane and then used for seeding the first and the third fractions. Thecrystalline product is recrystallized from hexane and for analyticalpurposes sublimed at C. under an oil pump pressure; it melts at ISO-151C. Optical rotation [a] =+ZO3i-Z (c.=0.41 in chloroform). Infraredabsorption bands (in methylene chloride) at 5.72, 5.90, 7.35, 8.23,8.55, 9.32, 9.90 and 10.35%

A further quantity of the desired compound can be identified in theabove crude product, but it is not isolated and is further worked upwithout previous purification.

EXAMPLE 5 2.9 grams of lead tetraacetate are given at once into asolution of 1.265 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-SB-(N,N'-dicarbomethoxy hydrozino)-thiazolidine-4-carboxylic acid methyl ester in 90 ml. of dry benzenecontaining 0.3 ml. of glacial acetic acid, and the mixture is refluxed.When the solid reagent has dissolved, a precipitate of lead diacetatebegins to form and about 2 hours later no oxidation reagent can bedetected any longer. The reaction mixture is filtered with the use of afilter aid (Celite), rinsed with benzene and the yellow filtrate isevaporated, repeatedly taken up in a mixture of benzene and heptane, andeach time the solvent mixture is evaporated until the acetic acid hasbeen completely removed.

The golden yellow, viscous-oily residue, containingL-2,2-dimethyl-3-tertiary butyloxycarbonyl-5-acetyloxy-5-carbomethoxyazo-thiazolidine-4-carboxylic acid methyl ester of theformula is chromatographed within 3 hours on 39' g. of a diatomaceousearth preparation (Florisil). Elution with benzene, ether and a mixtureof ether and methanol furnishes a crude product consisting predominantlyof L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Sli-acetyloxy-thiazolidine-4-carboxylic acid methylester which melts at to 148 C. after recrystallization from a mixture ofether, methylene chloride and hexane.

The subsequently eluted fractions and the mother liquor are combined,hydrolyzed with sodium acetate in methanol, and chromatographed on 60times the amount of silica-gel containing 5% of water. After Washingwith benzene containing 3% of ethyl acetate the L-2,2-di- 13methyl-3-tertiary butyloxycarbonyl-Sfi-hydroxy thiazolidine-4-carboxylicacid methyl ester of the formula o o 0H:

1130 CHs EXAMPLE 6 A mixture of 1.07 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl B(N,N'-dicarbomethoxy-hydrazino)-thiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester in 50 ml. of benzene containing 0.25 ml. ofglacial acetic acid and 1.75 g. of lead tetraacetate is refluxed for 45minutes. The cooled mixture is filtered, the solvent evaporated undervacuum and the residue taken up in 200 ml. of a 1:1- mixture of benzeneand heptane. The solvents are then evaporated and the residuechromatographed on g. of a diatomaceous earth preparation (Florisil).The oily L- 2,2 dimethyl-3-tertiary butyloxycarbonyl-5Bacetyloxythiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester ofthe formula is eluted with benzene. Optical rotation [u] =-}-49i1(c.=1.04 in chloroform). Infrared absorption bands (inrnethylenechloride) at 5.74, 5.90 and 8.25,u.

EXAMPLE 7 A solution of 0.14 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5,B-acetyloxy-thiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester in 3.5 ml. of 90% acetic acid is mixed with1.5 g. of zinc dust, and the reaction mixture is stirred for 4 hours atroom temperature. The batch is filtered and the residue rinsed with 4ml. of acetic acid and 200 ml. of benzene; the filtrate is Washed 5times with Water, dried over magnesium sulphate and evaporated. Theresidue crystallizes on being triturated with a mixture of pentane andether and is recrystallized from a mixture of ether and hexane. Theresulting L-2,2-dimethyl 3-tertiarybutyloxycarbonyl-Sfl-acetoxy-thiazolidine-4-carboxylic acid of theformula melts at l45l46 C. after having been sublimed at 127 C. under apressure of 0.001 mm. Hg. Optical rotation [a] =+225 (c. O.93 inchloroform). Infrared absorption bands (in methylenechloride) at 5.75,5.90 and 8.25 1..

EXAMPLE 8 A solution of 25.23 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5,8 (N,N-dicarbomethoxy-hydrazino)-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester in boil. Aftercooling and filtering the filtrate is evaporated in a Water-jet 'vacuumand the residue chromatographed I, on 750 g. of a diatomaceous earthpreparation (Florisil).

The crude mixture of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-acetyloxy-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester and its Sfi-acetoxy isomer is eluted with 2500 ml.of a 98:2-mixture of benzene and ethyl acetate. On crystallization frompentane there is obtained the L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-S/B-acetyloxy-thiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester melting at 87 C.

The mother liquor furnishes the non crystallizing L-2,2-dimethyl-3-tertiary butyloxycarbonyl 50cace-tyloxythiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester ofthe formula O O O O H2 0 Ola (3H /OHCH---O-COCHa EXAMPLE -9 A mixture of11.82 g. of L-2,2-din1ethyl-3-tertiary butyloxycarbonyl 55(N,N'-dicarbomethoxy-hydrazino)- thiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester in 150 ml. of benzene and 24.4 g. of leadtetraacetate is heated for 45 minutes at a gentle boil, cooled, filteredand evaporated under vacuum. The yellow, oily residue con tains theL-2,2-dimethyl-3-tertiary butyloxycarbonyl-5-acetyloxy-S-carbomethoxyazo thiazolidine 4-carboxylic acid2,2,2-trichloroethyl ester; it is taken up in 200 ml. of warm hexane,filtered, and the filtrate is evaporated. The residue is dissolved in250 ml. of benzene, mixed with 100 g. of a diatomaceous earthpreparation (Florisil) and 5 ml. of ethyl acetate and stirred forminutes. The batch is filtered and the filtrate evaporated, to yield acrude mixture of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-acetyloxy-thiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester and its 5,8-acetyloxy isomer.

EXAMPLE 10 A solution of the mixture obtained by the process describedin Example 9 in 200 ml. of glacial acetic acid and 20 m1. of water ismixed with 60 g. of zinc dust and stirred for 3 hours at roomtemperature. The mixture is then filtered and the filter residue washedwith 60 ml. each of glacial acetic acid and benzene. The filtrate isevaporated under 0.5 mm. Hg, the residue taken up in 600 ml. of etherand the solution washed with 600 ml. of water, and the aqueous phase isrinsed with ether. The combined ether solutions are twice washed withWater, dried and evaporated, and the residue dissolved in ether, treatedwith an active carbon preparation and crystallized from a mixture ofether and pentane, to yield L-2,2-dimethyl 3-tertiarybutyloxycarbonyl-SB-acetyloxy-thiazolidine-4-carboxylic acid melting at146-147 C.

The mother liquor is evaporated and the residue dissolved in methylenechloride and extracted With an aqueous sodium hydrogen carbonatesolution. The basic extract is acidified with citric acid and extractedwith methylene chloride. Fractional crystallization from a mixture ofpentane and ether furnishes the L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5a acetyloxy-thiazolidine-4-carboxylic acid of theformula M.P. 171-171.5 (3.; [a] =--346i1 (c.=0.925 in chloroform);infrared absorption spectrum (in methylenechloride) with bands at 2.87,3.15, 5.75, 5.90, 5.96,

15 7.25, 7.53, 8.25, 8.63 and 10.66 2; together with a major quantity ofa crystalline mixture of the two acids.

EXAMPLE 11 A mixture of 0.25 g. of L2,2-dimethyl-3-tertiarybutyloxycarbonyl 5p (N,N' dicarbethoxy-hydrazino)-thiazolidine-4-carboxylic acid N-acetylamide in 10 ml. Of boilingbenzene is treated with 0.45 g. of lead tetraacetate and refluxed for 60minutes. The reaction mixture is then concentrated under a water-jetvacuum to about '5 1111., diluted with 25 ml. of hexane and filtered.The filtrate is concentrated under vacuum and the yellow oily residuechromatographed on silica gel. The L-2,2-dimethyl- 3 tertiarybutyloxycarbonyl 5 acetyI-S-carbethoxyazothiazolidine-4-carboxylic acidN-acetylamide of the formula is eluted with a 9:1-mixture of benzene andethyl acetate. Treatment of the eluate with a diatomaceous earthpreparation (Florisil) furnishes a mixture of L-2,2-dimethyl- 3 tertiarybutyloxycarbonyl 5B acetyloxy-thiazolidine 4-carboxylic acidN-acetylamide of the formula C} ONH-C o-o Ha on. /('JH-CHOOO-CHsHaC-C-O-C-N i] H3 /C\ H3O CH3 and its m-acetyloxy isomer.

EXAMPLE 12 A solution of 0.831 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5,6-acetyloxy-thiazolidine-4-carboxylic acid in m1. ofmethylene chloride is mixed With 0.36 ml. of triethylamine, cooled to 10C. and treated with 0.25 ml. of chloroformic acid ethyl ester in 4 ml.of cold methylene chloride. The reaction mixture is kept for 90 minutesat -10 to *5 C. under anhydrous conditions and then treated for 3 hourswith a strong current of dry gaseous ammonia. The batch is kept for 10minutes at 0 C. and for 40 minutes at room temperature and thenfiltered, the filter residue rinsed with methylene chloride and thefiltrate evaporated. The residue is dissolved in 30 ml. of methylenechloride, and the solution is agitated with 5 g. of silica gelcontaining 5% of water and filtered. The silica gel is rinsed with9:1-mixtures and 5:1-mixtures of methylene chloride and alkyl acetate,to yield L-2,2- dimethyl 3 tertiarybutyloxy-carbonyl-5,8-acetyloxy-thiazolidine-4-carboxylic acid amide ofthe formula QONHa as a colourless glass which can be distilled at 125 C.130 C. under 0.001 mm. Hg pressure as a viscide, colourless oil.Infrared absorption bands (in methylene chloride) at 2.86, 2.96, 5.75,5.92, 6.38, 7.25, 8.25, 7.42, 8.25, 8.6 5, 9.2, 9.35, 9. 88 and 1040EXAMPLE 13 980 grams of lead tetraacetate are tipped into a solution of384 g. of L-2,2-dimethyl-3-tertiary butyloxycarbonyl- 5(N,N'-dicarbomethoxy-hydrazino)-thiazolidine-4-carboxylic acid methylester. The solution turns dark brown and is heated, whereupon it becomesgolden yellow and white lead diacetate begins to separate. The batch isstirred for 2 hours under reflux and 0.5 ml. of ethyleneglycol is added;the reaction mixture is filtered through a glass filter and the residuewashed with a total of 4000 to 5000 ml. of dry benzene. The combinedfiltrates are evaporated under vacuum and the yellow, oily residue istaken up in 3 500 ml. of dry benzene and the solvent is evaporated undervacuum each time. The slowly crystallizing residue is taken up inmethylene chloride, the solution filtered and evaporated. The -I'eacti0nproduct, consisting predominantly of a mixture of L-2,2-dimethyl-3-tertiary butyloxycarbonyl 5a acetyloxy-thiazolidine-4- carboxylic acidmethyl ester and its Sfl-acetyloxy isomer, as well as of2,2-dimethyl-3-tertiary butyloxycarbonyl-4- thiazoline-4-carboxylic acidmethyl ester and L-2,2-dimethyl-3 tertiarybutyloxycarbonyl-S-acetyloxy-S-carbomethoxyazo-triazolidine-4-carboxylicacid methyl ester, is further processed without further purification.

A solution of 363 g. of the product in 8000 ml. of dry methanol is mixedwith 150 g. of sodium acetate and the mixture is refluxed with stirringfor 24 hours and then cautiously evaporated under vacuum. The residue isstirred With 2 1500 ml. of benzene and each time evaporated to dryness,and then thoroughly extracted within 6 hours with a total volume of 5000ml. of methylene chloride. The organic solution is evaporated and theresulting dark brown oil dissolved in 1000 ml. of dry benzene andchromatographed on 1900 g. of silica gel containing 5% of water, in eachcase collecting fractions of 2000 ml., 16,000 to 18,000 ml. of benzene,containing 3 of ethyl acetate elute in the first place apolarby-products; subsequent elution with 40,000 ml. of benzene containing 5%of ethyl acetate and 8000 ml. of benzene containing 10% of ethyl acetatefurnishes the L-2,2-dimethyl-3-tertiary butyloxycarbonyl 5Bhydroxy-thiazolidinel-carboxylic acid methyl ester of the formula in theform of a yellow oil which crystallizes from hexane containing a traceof ether as an almost White product melting at 10l102 C. (after dryingfor 3 hours at C., under 0.01 mm. Hg pressure). Optical rotation [a];y=|48i1 (c.=1.14 in chloroform). Infrared absorption bands (inmethylene chloride) at 2.80, 5.75, 5.95, 7.35, 8.65 and 935111.; endabsorption in the ultraviolet spectrum (in methanol). The resultingmother liquor is once more chromatographed on silica gel to yield afurther amount of the desired product.

Eluted as polar by-products are in the first place the2,2-dimethyl-3-tertiary butyloxycarbonyl 4-thiazoline-4- carboxylic acidmethyl ester boiling at 65 C. under 0.001 mm. Hg pressure and melting at3436.5 C.; infrared absorption bands (in methylene chloride) at 5.88,6.37, 7.34, 7.45, 7.62, 8.24, 8.65, 8.85, 9.32 and 11.91 ultravioletabsorption bands (in ethanol) k 270 m (5:5320) and 316 mu (e=5960), andthe L-2,2-dimethyl- 3-tertiarybutyloxycarbonyl-4-hydroxy-thiazolidine-S-one- 4-carboxylic acid methylester melting at 113.51l4 C. Optical rotation [a] =-l:1 (in chloroform).Infrared absorption bands (in methylene-chloride) at 2.85, 5.70, 5.85,7.60, 8.95, 10.25 and 1045a. Ultraviolet absorption .bands (in 96%ethanol) :237 m EXAMPLE 14 A solution of 0.084 g. ofL-2,2-dimethyl-3-tertiary butyloxycarbonyl-5a acetyloxythiazolidine-4-carboxylic acid in 0.56 ml. of l N sodium hydroxidesolution is kept for 2 hours at room temperature, then mixed with 0.13g. of citric acid and repeatedly extracted with methylenechloride. Theorganic extracts are evaporated to yield 17 L-2,2-dimethyl-3-tertiarybutyloxycarbonyl B-hydroxy thiazolidine-4-carboxylic acid of the formulaoooH CH3 CH-CHOI-I which melts at 185 C. on recrystallization from amixture of ether and pentane. Optical rotation [a] 127 :1 (c.=0.8 in 1 Nsodium hydroxide solution). Infrared absorption bands (in potassiumbromide) at 2.82, 5.75, 6.02, 7.25, 8.02, 8.40, 8.65, 9.20, 9.70, 10.89,11.65, 12.90 and 13.30 2.

EXAMPLE melting at 185 C. Optical rotation [oc] =|-123i1 (c.=1 in l Nsodium hydroxide solution).

EXAMPLE 16 0.035 gram of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Sfi-hydroxy-thiazolidine-4-carboxylic acid in 2 ml. ofether is treated with an ether solution of diazomethane, and the crudeproduct is dissolved in a 9:1-mixture of benzene and ethyl acetate andfiltered through 1.2 g. of silica gel, to yield pureL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5,8-hydroxy-thiazolidine-4-carboxylic acid methyl esterwhich is identical with the product obtained by the process of Example13.

EXAMPLE 17 A solution of 0.323 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5p acetyloxy-thiazolidine-4-carboxylic acid amide in 2ml. of methanol is mixed with 1 ml. of 1 N sodium hydroxide solution,then kept for 160 minutes at room temperature, evaporated to half itsvolume under vacuum and extracted with methylene chloride. The resultingcrude product obtained on evaporation consists predominantly ofL-2,2-dimethyl-3-tertiary butyloxycarbonyl-Sfi-hydroxythiazolidine-4-carboxylic acid amide of the formula whose infraredspectrum (in methylene chloride) contains bands at 2.80, 2.87, 2.95,5.95, 6.40, 7.25, 7.35, 7.45, 8.65, 9.20, 9.35, 9.83 and 11.66

EXAMPLE 18 A mixture of 6.24 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5-(N,N dicarbomethoxyhydrazino)-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester and60 ml. of benzene is treated with 10.33 g. of lead tetraacetate andrefluxed for 30 minutes. After cooling and filtering, the filtrate isevaporated under vacuum, to yield a yellow, oily residue consistingpredominantly of a mixture of L-2,2-dimethyl-3-tertiary butyloxycarbonyl50cacetyloxy-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl esterand its 5,8-acetyloxy isomer, as Well as the L-2,2-dimethyl 3 tertiarybutyloxycarbonyl-S-acetyloxy-5-carbomethoxyazo-thiazolidine-4-carboxylic acid 2,2,2- trichloroethylester; this mixture is further worked up without being further purified.

By chromatography of the resulting product mixture on 180 g. of adiatomaceous earth preparation (Florisil) and elution with 1000 ml. of a98:2-mixture of benzene and ethyl acetate there is obtained as the mainproduct L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-Sfi-acetoxy-thiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester, whereas subsequent fractions eluted with thesame solvent mixture furnish L-2,2-dimethyl-3-tertiary butyloxycarbonyl-Sfi-hydroxy-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester ofthe formula o o 0 onto on CH3 orr orron 11.0-4'3-0-0-8/ s CH3 ii o 1130orn as a colourless oil boiling at 115 C. under 0.005 mm. Hg pressure.Infrared absorption bands (in methylene chloride) at 2.75, 5.65, 5.72,5.85, 5.90, 7.35, 8.60, 9.16, 9.32, 9.78 and 11.6].L.

EXAMPLE 19 A solution of 0.274 g. of crude L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5a-acetyloxy-thiazolidine-4-carboxylic acidN-methyl-N-phenylsulphonylamide in 3 ml. of dimethylformamide is mixedwith 0.05 ml. of anhydrous hydrazine and the mixture is stirred for 5hours at room temperature, then poured into 30 ml. of saturated sodiumchloride solution and extracted three times with ml. of methylenechloride in 3 portions. The organic extract is once washed withsaturated sodium chloride solution and evaporated. The crude product isdissolved in 40 ml. of methylene chloride and washed with 2x 30 ml. of10% aqueous citric acid solution and once with 30 ml. of water. The acidextracts are adjusted with aqueous ammonia to pH about 9 and extractedwith 3X 40 ml. of methylene chloride. The organic extracts areevaporated and the crystalline residue is recrystallized from a mixtureof ether and pentane, to yield L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-SB-hydroxy-thiazolidine-4-carboxylic acid hydrazine ofthe formula which after recrystallization melts at 154-155 C. Opticalrotation [a], =+l6i1 (c.=1.119 in chloroform). Infra-red absorptionbands (in methylene cholride) at 2.78, 2.92, 3.03, 6.00, 6.19, 7.25,7.36, 7.50 and 8.14

EXAMPLE 20 By treating a benzene solution of L-2,2-dimethyl-3- tertiarybutyloxycarbonyl 5-acetyloxy-S-carbomethoxyazothiazolidine 4-carboxylicacid N-methyl-N-phenylsulphonylamide with a diatomaceous earthpreparation (Florisil), there is obtained, in addition to a mixture ofthe 5u-acetylloxy and S/E-acetyloxy isomers of L-2,2- dimethyl3-tertiary butyloxycarbonyl-S-acetyloxy-thiazolidine 4-carboxylic acidN-methyl-N-phenylsulphonylamide, also the L-2,2-dimethyl-3-tertiarybutyloxycar- 19 bonyl 55 hydroxy thiazolidine-4-carboxylic acid N-methyl-N-phenylsulphonylamide of the formula melting at 177 to 181 C.Infrared absorption bands (in methylene chloride) at 2.80, 2.99, 3.44,5.90, 5.98, 7.42, 8.30, 8.62, 9.20, 9.38, 9.82, 9.94 and 10.78

EXAMPLE 21 A solution of 0.322 g. of diphenyldiazomethane in m1. etheris added dropwise over a period of minutes and while stirring to asolution of 0.456 g. of L-2,2- dimethyl 3 tertiarybutyloxycarbonyl-Sp-hydmxy-thiazolidin-4-carboxylic acid in 7 ml. ofether. The reaction mixture is allowed to stand over night, thenfiltered and the filtrate is evaporated under reduced pressure. Theresulting yellowish syrup is chromatographed on 39 g. of silica gel; thecolumn is prepared with benzene and 50 ml. fractions are taken, a19:1-mixture of benzene and ethyl acetate being used for the elution.Fractions 4-8 are evaporated and combined and the product dried overnight at 50 C./0.01 mm. Hg to yield the glass-like yellowishL-2,2-dimethyl-3-tertiary butyloxycarbonyl-5phydroxythiazolidine-4-carboxylic acid diphenylmethylester of the formula whichin the infrared spectrum (in methylene chloride) shows bands at 2.75,3.45, 5.72, 5.90 and 7.35,.

'EXAMPLE 22 A solution of 0.104 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 3-tertiary butyloxycarbonyl-5,8-acetyloxy thiazolidin 4carboxylic acid-N-phenylsulfonylamide in 2 ml. of dioxan is diluted with2 ml. of water, cooled with ice and, while stirring, quickly treatedwith 4.54 ml. of an 0.1 N sodium hydroxide solution. The solution isstirred at 0 C. during 10 minutes, diluted with 50 ml. of methylenechloride and washed with 10 ml. of a 10% aqueous citric acid solutionand with 50 ml. of water, dried and evaporated. The residue iscrystallized from a mixture of ether and pentane to yield the L2,2-dimethyl-3-tertiarybutyloxy-carbonyl-55-hydroxythiazolidin-4-carboxylicacid-N-phenyl-sulfonylamide of the formula 0 oNHso2 which melts at164-165 C. after recrystallization from methylene chloride and hexane;[a] =26il (0. =1.62 in chloroform); infrared absorption spectrum (inmethylene chloride) with bands at 2.75, 3.00, 5.85 and 6.07

The starting material is prepared by reacting L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-SB-acetyloxythiazolidine-4-carboxylic acid (Example 7)with phenyl sulfonylisocyanate in the presence of triethylamine and drybenzene as the solvent. The L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5B-acetyloxy-thiazolidine-4-carboxylic acid-N-phenylsulfonylamide of the formula melts at 150152 C. afterrecrystallization from a mxit ure of methylenechloride, ether andpentane; [a] =+57 il (c.=1.032 in chloroform); infrared absorptionspectrum (in methylene chloride) with bands at 3.0, 5.73, 5.83, 5.95,6.07, 7.06, 7.25, 7.34, 8.20, 8.43, 8.50, 9.20, 9.85 and 10.36ultraviolet absorption spectrum (in ethanol) with A at 223 m (e=23,000),260 mu (6 810) 267 m (e=1100) and 273 mp (6 920).

EXAMPLE 23 A solution of 5 g. of L-2,2-dirnethy1-3-tertiarybutyloxycarbonyl-5 S-acetyloxy-thiazolidine-4-carboxylic acid methylester in 150 ml of a 1:1-mixture of tetrahydrofuran and methanol iscooled to 15 C. and slowly treated with 30 ml. of a 0.5 N aqueous sodiumhydroxide solution; the addition takes about 1 hour. After acidifyingthe reaction mixture with 2 ml. of acetic acid (pH about 6) andevaporating it under reduced pressure to a volume of about 50 ml.; atotal of 200 ml. of water is slowly added while stirring. As soon as anoily precipitate is formed, the reaction mixture is seeded with a smallamount of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Sfl-hydroxythiazolidine-4-carboxylic acid methyl esterand cooled, while continuing the addition of the Water. After stirringfor 1 hour at 0, the mixture is filtered; the solid material is driedover calcium chloride under reduced pressure and at room temperature.The resulting crude L-2,2-dimethyl- 3 tertiary butyloxycarbonyl 5 ,8hydroxythiazolidine-4- carboxylic acid methyl ester melts at 9899 andmay be used without further purification. By extracting the filtratetwice with 100 ml. of methylene chloride one obtains a further amount ofthe desired hydroxy ester in crude form.

It can also be purified as follows: A mixture of 21.4 g. of the crudeL-2,2-dimethyl-3-tertiary butyloxycarbonyl-SB-hydroxy-thiazolidine-4-carboxylic acid methyl ester and ml. of etheris concentrated to 80 ml., diluted with ml. of hexane and concentratedunder normal pressure to 100 ml. After seeding the temperature is slowlybrought to room temperature and the mixture is allowed to stand at 10over night. The precipitate is filtered off to yield theL-2,2-dimethyl-3-tertiary butyloxycarbonyl-Sfl-hydroxythiazolidine-4-carboxylic acid methyl ester melting atl00103.

EXAMPLE 24 A solution of 1.145 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5/3 hydroxy-thiazolidine-4-carboxylic acid methyl esterin 30 ml. of ethanol-free methylene chloride is treated with 30 ml. oftriethylamine and then during 2 minutes with phosgene. The mixturestarts to boil and triethylammonium chloride precipitates; it isimmediately concentrated under reduced pressure to about 5 g. to ahalf-crystalline residue which is extracted several times with warmether. After filtering, the organic solvent is concentrated under waterpump vacuum and the oily residue, containing theL-2,2dimethyl-3-tertiarybutyloxycarbonyl-5-chlorothiazolidine-4-carboxylic acid methyl ester ofthe formula is dissolved without further purification in 20 ml. ofacetic acid and stirred with 2 g. of sodium acetate. The clear solutionis becoming turbid (precipitation of sodium chloride) and after 2 hours,the dispersion is evaporated under reduced pressure; at the end a smallamount of toluene is added, and also evaporated. The residue is taken upin 50 ml. of water and 50 ml. of methylene chloride, the organic phaseis washed twice with 50 ml. of water, dried and evaporated under reducedpressure. The oily residue crystallizes and is taken up in ml. of a 1:1-mixture of hexane and pentane. The crystalline product is filtered offand represents the L-2,2-dimethyl-3-tertiary butyloxycarbonyl5B-acetyloxy-thiazolidine-4-carboxylic avid methyl ester, which melts at145l4 8 after washing with pentane.

The hexane-pentane-solution is evaporated and the oily residue ischromatographed on 50 g. of silica gel, the column being prepared withbenzene:

Weight Fraction Solvent M1. (in g.)

1 Benzene 100 0.001 100 0.001

Fractions 5-8 are taken together and distilled: the desired L 2,2dimethyl 3 tertiarybutyloxycarbonyl-5aacetyloxy-thiazolidine-4-carboxylic acid methyl esterof the formula QOOCHs A solution of 20 g. of the crystallineL-2,2-dimethyl- 3-tertiary butyloxycarbonyl-55-acetyloxy-thiazolidine 4-carboxylic acid methyl ester and '8 g. of anhydrous sodium acetate in400 ml. of anhydrous methanol is stirred at room temperature underexclusion of mixture. Stirring is discontinued, as soon as a clearsolution is obtained; the latter is allowed to stand at room temperaturefor 10 days and is then concentrated to a volume of about 100' ml. and,while cooling with ice, slowly treated with 400 ml. of water. As soon asan oily precipitate is formed, the mixture is seeded with a small amountof L-2,2-dimethyl- 3 tertiarybutyloxycarbonyl-5,8-hydroxy-thiazolidine-4- carboxylic acid methylester; after completion of the water addition the reaction mixture isstirred at 0 for another 30 minutes, then filtered and the residuewashed with water and dried for 3 days over calcium chloride at mm.pressure. The resulting L-2,2-dimethyl-3-tertiary butyloxycarbonyl 55hydroxy-thiazolidine-4-carboxylic acid methyl ester melts at 9295.

From the aqueous extracts a further amount of the crude hydroxy-estercan be obtained by extraction with methylene chloride; the crudematerial can be purified as follows: 4.8 g. of the crudeL-2,2-dimethyl-3-tertiary butyloxycarbonyl-5fl-hydroxy-thiazolidine 4carboxylic acid methyl ester in ml. of hexane is filtered through acolumn of 24 g. of silica gel containing 5% of water. After washing withml. of hexane, the column is eluted with 20 0 ml. of a benzene-ethylacetate mixture; the resulting product melts at 9498.

EXAMPLE 26 A solution of 0.773 g. of the crystalline L-2,2-dimethyl- 3tertiary butyloxycarbonyl 5B acetyloxy thiazolidine-4-carboxylic acid2,2,2-trichloroethylester in 12 m1. of methanol is cooled to -10 andtreated over a period of 2 minutes with 1.72 ml. of a 1 N aqueous sodiumhydroxide solution. After stirring for 18 minutes, the reaction mixtureis poured into ice-cooled 2 N aqueous citric acid and the mixture isextracted with methylene chloride. The colorless oil obtained afterevaporating the organic solution is chromatographed on 10 g. of silicagel containing 5% water. A small amount of 2,2-dimethyl- 3 tertiarybutyloxycarbonyl-4-thiazoline-4-carboxylic acid2,2,2-trichloroethylester is eluted with benzene; with methylenechloridethe main fraction, i.e. the L-2,2-dimethyl 3tertiary-butyloxycarbonyl-SB-hydroxythiazolidine-4-carboxylic acid2,2,2-trichloroethylester is washed out, whereas the transesterificationproduct, i.e. the L-2,2- dimethyl 3 tertiarybutyloxycarbonyl-Sfi-hydroxythiazolidine-4-carboxylic acid methylesteris eluted with methylenechloride containing 10% of methanol. The L- 2, 2dimethyl-3-tertiary-butyloxycarbonyl-Sfl-hydroxythiazolidine 4carboxylic acid 2,2,2-trichloroethylester crystallizes from aconcentrated solution in n-hexane and melts at l04l05.

What is claimed is: 1. A S-acyloxy-thiazolidine of the formula I}!CH-CH-OH A0rN S wherein Ac is an easily eliminable acyl residue of asemiester of carbonic acid, X stands for the group of the formula R2 Rsin which each of the groups R and R is lower alkyl, and R represents amember selected from the group consisting of a carboxyl, carboxylesterified by lower alkanol, carboxyl esterified by halogeno-loweralkanol, carboxyl esterified by phenyl-lower alkanol, carbamyl, N-loweralkanoyl-carbamyl, N-phenylsulfonyl-carbamyl, N-phenylsulfonyl-N-loweralkyl-carbamyl and hydrazinocarbonyl.

2. A compound as claimed in claim 1 and being a compound of the formulaBi CHCE-OH Aer-N HaC CH3 in which Ac is the acyl residue of a semiesterof carbonic acid, and R is a member selected from the group consistingof a free carboxyl group, a carboxyl group esterified with a loweralkanol and a carboxyl group esterified with a halogenated loweralkanol.

3. A compound as claimed in claim 1 and being L-2,2- dimethyl-S-tertiarybutyloxycarbonyl-Sfi-hydroxy-thiazolidine-4-carboxylic acid methylester.

4. A compound as claimed in claim 1 and being L-2,2- dimethyl 3 tertiarybutyloxycarbonyl-Slit-hydroxy- 23 2'4 thiazolidine 4 carboxylic acid2,2,2-trichloroethy1 3,159,617 12/1964 Sheehan et a1. 260306.7 XR ester.3,399,207 8/1968 Bamberg et a1. 260-306] 5. A compound as claimed inclaim 1 and being L-2,2-

dimethyl 3 -tertiary butyloxycarbonyl 55 hydroxy- OTHER REFERENCESthiaz01idine-4-carboxylic acid diphenylmethyl ester. r Strukov: C.A.,v01. 47, pp. 2755-2756 (1953).

Wagner et a1.: Synthetic Organic Chemistry, p. 169

References Cited (1953) UN STATES A T Woodward et 8.1.! J. Am. Chem.800., V01. 88, pp. 852- 2,450,784 10/1948 Dufiin et a1. 260306.7 XR 853(1966).

2,480,079 8/1949 Hunter et a1. 260-306.7 XR 10 OY D. HIG L PrimaryExaminer 2,580,931 1/1952 Lane 260537 2,721,869 10/1955 DAmico 260306.7US. Cl. X.R. 2,952,673 9/1960 Benghiat et a1. 260-158 260158, 243, 483

